Synthesis of d-2-amino-1-butanol

ABSTRACT

D-2-Amino-1-butanol, for the synthesis of ethambutol hydrochloride, d,d&#39;-2,2&#39;-(ethylenediimino)di-1-butanol dihydrochloride, is produced in high purity and good yields by the reaction of butene-1, a nitrile, preferably an excess of acetonitrile, and chlorine to form N-[1-(chloromethyl)propyl]acetimidoyl chloride which is hydrolyzed to dl-2-amino-1-butanol, which can be isolated as the hydrochloride, or free base, or a mixture, resolved with L(+)- tartaric acid and the d-2-amino-1-butanol reacted with ethylene dichloride and then hydrochloric acid to form ethambutol hydrochloride. A minimum of by-products which are conveniently split out permits the economical synthesis of a pharmaceutical grade product.

BACKGROUND OF THE INVENTION

Ethambutol hydrochloride, which isd,d'-2,2'-(ethylenediimino)di-1-butanol dihydrochloride is a therapeuticagent for the treatment of tubercle bacilli infections, particularlyhuman tuberculosis caused by Mycobacterium tuberculosis. The compound,its preparation, and its therapeutic use are disclosed in U.S. Pat. No.3,176,040, 1965, Wilkinson and Shepherd, see Example 2 thereof. Thetherapeutic activity of the d-isomer is discussed in J. Am. Chem. Soc.83, 2212 (1961).

The d,d-form of ethambutol may be made by reacting ethylene dichloridewith d-2- amino-1-butanol. The ethambutol can be separated as the base,and converted to the dihydrochloride salt.

One method of resolving aminobutanol is disclosed in U.S. Pat. No.3,553,257, Jan. 5, 1971, Halmos and Ricketts.

U.S. Pat. No. 3,769,347, Oct. 30, 1973, John Kazan, PRODUCTION OFd,d'-2,2'-(ETHYLENEDIIMINO)DI-1-BUTANOL HYDROCHLORIDE, details certainprocesses for the improvement of yields and purity. Said patents andpublications are herein hereby incorporated by this reference thereto.

PRIOR ART

U.S. Pat. No. 2,569,549, Oct. 2, 1951, P. L. Barrick, IMIDOHALIDES ANDPROCESS OF PREPARING THEM AND THEIR HYDROLYSIS PRODUCTS, discloses thepreparation of imidohalides of N-acyl-beta-haloamines. Among much otherdisclosure, Example VIII discloses the reaction of 56 parts (0.5 mole)of octene-1, 41 parts (1 mole) of acetonitrile and 55 parts (0.77 mole)of chlorine at 10°-15° C., with the reaction mixture being poured intoice and water, treated with concentrated hydrochloric acid, and steamdistilled.

The product reported is 14 parts of the hydrochloride of1-hydroxymethylheptylamine ##EQU1## produced by the complete hydrolysisof the intermediate imidochloride ofN-[(alpha-hexyl-beta-chloro)ethyl]acetamide. Using the nomenclature ofthis case, these would be named dl-2-amino-1-octanol hydrochloride andN-[1-(chloromethyl)heptyl]acetimidoyl chloride. Column 12, line 75,mentions butene-1, among other starting materials.

Example VI of said U.S. Pat. No. 2,569,549 shows the addition ofisobutylene to a solution of 32 parts of chlorine in 135 parts ofacetonitrile, until the yellow color disappeared. Excess acetonitrilewas removed, and the product was hydrolyzed with dilute hydrochloricacid to produce an N-(chloroisobutyl)trichloroacetamide, probablyN-[(beta-chloro-alpha, alpha-di-methyl)ethyl]trichloroacetamide.

SUMMARY OF THE INVENTION

Butene-1 and chlorine are added to acetonitrile, preferablysimultaneously, to yield N-[1-(chloromethyl)propyl]acetimidoyl chloridetogether with a certain amount of byproduct 1,2-dichlorobutane. TheN-[1-(chloromethyl)propyl]acetimidoyl chloride may be hydrolyzed in situto N-[1-(chloromethyl)propyl]acetamide, which is further hydrolyzed withpresumably ring closing and reopening steps to dl-2-amino-1-butanol,conveniently as the hydrochloride. In the presence of a lower alkanol,the dl-2-amino-1-butanol hydrochloride may be partially neutralizedwithh ammonia with the aminobutanol being separated as about atwo-thirds mixture of dl-2-amino-1-butanol with dl-2-amino-1-butanolhydrochloride which is a particularly convenient ratio for the feed forreaction with tartaric acid to resolve the dl-2-amino-1-butanol.

This gives d-2-amino-1-butanol in a form which is particularlyacceptable for reaction with ethylene dichloride to yield apharmaceutically elegant grade ofd,d'-2,2'-(ethylenediimino)di-1-butanol dihydrochloride. These equationsmay be written: ##EQU2## N-[1-chloromethyl)propyl]acetimidoyl chlorideor N-[1-(chloromethyl)propyl]ethanimidoyl chloride ##EQU3##N-[1-(chloromethyl)propyl]acetamide ##SPC1##

4-ethyl-2-methyl-2-oxazoline hydrochloride or4,5-dihydro-4-ethyl-2-methyl-oxazole hydrochloride ##EQU4##

Surprisingly, best results are obtained in the reaction withacetonitrile if an excess of acetonitrile is used. Acetonitrile is theexpensive component and routinely it is customary to attempt to use lessof the expensive component.

Here, chlorine also reacts with butene-1 to yield 1,2-dichlorobutene. Anexcess of acetonitrile shifts the reaction towardsN-[1-(chloromethyl)propyl]acetimidoyl chloride. An amount of watercorresponding to that required for the hydrolysis ofN-[1-(chloromethyl)propyl]acetimidoyl chloride may be added before, withor after the addition of the chlorine and butene to the reaction mixtureto hydrolyze the N-[1-chloromethyl)propyl]acetimidoyl chloride toN-[1-(chloromethyl)propyl]acetamide. The reaction of acetonitrile withhydrochloric acid formed in the hydrolysis is sufficiently slow that atleast 95% of the excess of acetonitrile may be distilled under reducedpressure from the reaction mixture and recycled. The economical recoveryof the acetonitrile in such form that it may be recycled to the processis essential to the low cost production being sought.

Too great an excess of acetonitrile requires too large a reactionvessel. A continuous reaction may be used, which permits smallerequipment, and a large excess of acetonitrile, which is recycled to thestarting materials.

After stripping the acetonitrile, if hydrolysis ofN-[1-(chloromethyl)propyl]acetimidoyl chloride toN-[1-(chloromethyl)propyl]acetamide has not been completed during thereaction, hydrolysis is completed by adding water to the pot residue.Production of N-[1-(chloromethyl)propyl]acetamide by hydrolysis ofN-[1-(chloromethyl)propyl]acetimidoyl chloride, is favored by thepresence of a weak base such as calcium carbonate, calcium oxide,calcium hydroxide, sodium carbonate, sodium bicarbonate, potassiumcarbonate or bicarbonate, barium carbonate, or strontium carbonate. Thebase is not necessary if the N-[1-(chloromethyl)propyl]acetamide is tobe processed by further hydrolysis to dl-2-amino-1-butanol. Afterhydrolysis, 1,2-dichlorobutane is stripped by distillation under reducedpressure.

After removal of the acetonitrile and 1,2-dichlorobutane, the purity ofthe N-[1-(chloromethyl)propyl]acetamide is sufficiently high forconvenient processing through to dl-2-amino-1-butanol hydrochloride of agrade which may be used in a resolution step, or other purposes.

The N-[1-(chloromethyl)propyl]acetimidoyl chloride may be recovered andutilized after its formation. Conveniently, water is added to thereactor to hydrolyze N-[1-(chloromethyl)propyl]acetimidoyl chloride toN-[1-(chloromethyl)propyl]acetamide, so that, in effect, the first twosteps are simultaneously accomplished, exotherms are better controlled,and the processing steps are simultaneous, saving time and manipulation.A slight excess over the calculated quantity of water necessary forhydrolysis of N-[1-(chloromethyl)propyl]acetimidoyl chloride toN-[1-(chloromethyl)propyl]acetamide may be added after the completion ofchlorination.

The acetonitrile may be separated from theN-[1-(chloromethyl)propyl]acetimidoyl chloride orN-[1-(chloromethyl)propyl]acetamide. Conveniently, it is separated afterthe hydrolysis to N-[1-(chloromethyl)propyl]acetamide. The1,2-dichlorobutane may be separated in whole or in part by distillationafter the synthesis of N-[1-(chloromethyl)propyl]acetimidoyl chloride,or after hydrolysis to N-[1-(chloromethyl)propyl]acetamide. At leastpart of the 1,2-dichlorobutane may be retained until the synthesis ofthe dl-2-amino-1-butanol hydrochloride is completed. It is usually moreconvenient to separate the 1,2-dichlorobutane after the hydrolysis tothe N-[1-(chloromethyl)propyl]acetamide, as the reaction mixture is thensmaller, and more compact equipment may be used for the reaction of theN-[1-(chloromethyl)propyl]acetamide to dl-2-amino-1-butanolhydrochloride. Azeotropic distillation with water permits convenient andeffective complete removal of the 1,2-dichlorobutane from thedl-2-amino-1-butanol.

Subsequently, methanol is added to the aqueous reaction mixturecontaining N-[1-(chloromethyl)propyl]acetamide, preferably withcatalytic amounts of hydrochloric acid, which is refluxed to hydrolyzeto dl-2-amino-1-butanol hydrochloride with by-product methyl acetate.The methyl acetate is removed by distillation leavingdl-2-amino-1-butanol hydrochloride.

For the production of N-[1-(chloromethyl)propyl]acetimidoyl chloride,the presence of water is to be avoided, and vacuum distillation toremove acetonitrile and 1,2-dichlorobutane is necessary. If hydrolyzedto N-[1-chloromethyl)propyl]acetamide, mild conditions for the removalof both acetonitrile and 1,2-dichlorobutane are preferred. A weak baseaids in controlled hydrolysis. Where hydrolysis to dl-2-amino-1-butanolis desired, the acid produced in hydrolysis can be used to form thehydrochloride salts of the product.

In the production of dl-2-amino-1-butanol hydrochloride, theacetonitrile should be vacuum distilled out at theN-[1-(chloromethyl)propyl]acetamide stage, for recycling. If theacetonitrile is permitted to remain during the hydrolysis todl-2-amino-1-butanol hydrochloride, the acetonitrile tends to hydrolyzeto acetic acid with production of ammonia, usually as the ammoniumchloride. The acetic acid from the hydrolysis of acetonitrile is readilyremoved as the methyl ester, but the loss of acetonitrile reduces theefficiency of the process.

1,2-dichlorobutane is preferably at least partially removed by vacuumdistillation at the N-[1-(chloromethyl)propyl]acetamide stage. It causesno complications other than increasing the size of the reactor required.Conveniently, the last of the 1,2-dichlorobutane is removed byazeotropic distillation from dl-2-amino-1-butanol hydrochloride at thetime acetic acid is removed as the methyl ester. Conveniently, theintermediate reactions to dl-2-amino-1-butanol hydrochloride may overlapwithout the isolation of N-[1-(chloromethyl)propyl]acetimidoyl chlorideand N-[1-(chloromethyl)propyl]acetamide.

By dissolving in methyl alcohol, or isopropanol, or mixtures thereof, asolution of the dl-2-amino-1-butanol, predominantly as thehydrochloride, is obtained which can be partially neutralized withammonia to form a mixture of dl-2-amino-1-butanol anddl-2-amino-1-butanol hydrochloride, with ammonium chloride beingfiltered out. The mixture is approximately two partsdl-2-amino-1-butanol and one part dl-2-amino-1-butanol hydrochloride, aratio which is close to the optimum desired for reacting withL(+)-tartaric acid in the presence of anhydrous methanol to permit theseparation of the d-2-amino-1-butanol tartrate as is set forth in detailin U.S. Pat. No. 3,553,257, supra.

This process has unique and unexpected advantages in the present systembecause part of the butene-1 adds chlorine and acetonitrile in thereverse of the desired position so that about 3 to 10%dl-1-amino-2-butanol is found in the dl-2-amino-1-butanol as animpurity. In separation of the d- and l- isomers ofdl-2-amino-1-butanol, both isomers of dl-1-amino-2-butanol remain withthe mother liquor, and a much purified d-2-amino-1-butanol separates outas the L(+)-tartrate salt.

A starting material containing up to about 10% of dl-1-amino-2-butanolyields a purified d-2-amino-1-butanol, as the tartrate, having a contentof less than 0.01% of dl-1-amino-2-butanol, as its tartrate salts. Ifwashing is less thorough, up to 0.1% may be present. A purity is readilyobtained which can be used as a starting material for ethambutol whichis of pharmaceutical grade with a minimum of additional purification.

The facility of separating out impurities and byproducts is unobviousand of the essence of the present system of reactions.

EXAMPLE I Preparation of dl-2-Amino-1-butanol Hydrochloride

Acetonitrile (164 g., 4 moles) is placed in a tared 500 ml 4-neckedMorton flask equipped with a mechanical stirrer, a thermometer, twofritted glass gas-inlet tubes, a syringe needle (attached to a syringepump), and a dry-ice condenser. The flask is cooled in an ice-water bathto 3°-5° C. Chlorine (71 g., 1 mole) and butene-1 (56 g. 1 mole) arepassed through the well-stirred acetonitrile at a rate of about 400ml./min. each while water (10 g., 0.55 mole) is added simultaneously ata linear rate with the syringe pump during the course of the reaction (1hour).

The reaction temperature rises to 20° C. within 8 minutes and staysconstant through the course of the reaction. The reaction mixture isstirred for an additional 15-30 minutes. The reaction mixture is weighedto insure that proper amounts of the gaseous reactants have beenintroduced. Excess acetonitrile (b.p. 36°-41° C./150-170 mm.) is removedby distillation (bath temperature up to 100° C.) while using a 10-platedistillation column. A sudden temperature drop indicates the end ofacetonitrile distillation.

The acetonitrile fraction contains 1-2% HCl and about 6%1,2-dichlorobutane and can be recycled, without further treatment to asubsequent batch, or can be purified before recycling.

The head temperature rises to 70° and by-product 1,2-dichlorobutane isdistilled off between 70°-40° C. at 150 to 25 mm. A dry-ice trapattached to the vacuum line contains 15-25 g. of a material whichconsisted of 35% HCl, 10% 1,2-dichlorobutane and a crystalline solidderived from the reaction of acetonitrile with anhydrous HCl.

The residue in the flask, predominantlyN-[1-(chloromethyl)propyl]acetamide, is mixed with water (45 g. 2.5moles) and the mixture is brought to reflux. The residual1,2-dichlorobutane is removed by azeotropic distillation (Dean-Starktrap) while the mixture is refluxed for 2 hours. The water and someacetic acid (formed during hydrolysis with water) are removed at 80°(under reduced pressure (15-20 mm.) to leave a viscous residueconsisting of N-[1-(chloromethyl)propyl]acetamide, and its hydrolysisproducts.

Methanol (48 g., 1.5 moles) and concentrated hydrochloric acid (0.5 ml)are added to the residue and the reaction mixture is refluxed for 2hours. After removal of the volatiles (H₂ O, methyl acetate, etc.), thedl-2-amino-1-butanol hydrochloride is obtained as a colorless viscousmaterial which crystallizes on standing.

EXAMPLE 2 dl-2-amino-1-butanol

A 30 g. portion of the crude dl-2-amino-1-butanol hydrochloride fromExample 1 is suspended in a mixture of 100 ml. of toluene and 20 ml. ofisopropanol. Anhydrous ammonia (10.2 g., 0.6 mole) is introduced overthe surface of the well-stirred suspension at 25° C. A dry ice-acetonecondenser controls ammonia loss during reaction. Crystalline ammoniumchloride starts precipitating immediately and stirring is continued for15-20 minutes to insure completion of the reaction. The dry ice-acetonecondenser is removed and excess NH₃ is allowed to volatilize (15-20minutes). The precipitated NH₄ Cl is filtered off and washed with asmall amount of toluene.

The filtrate and washings are combined and the solvents evaporated underreduced pressure to obtain, d,l-2-amino-1-butanol (21.0 g.). The productby gas liquid chromatography is 63% pure, and contains about 8% ofdl-1-amino-2-butanol. The same process can be used to obtain the d- orl- optical isomer as free base from its hydrochloride salt.

EXAMPLE 3 d-2-amino-1-butanol tartrate from dl-2-amino-1-butanolhydrochloride

A 50 g. sample of dl-2-amino-1-butanol hydrochloride from Example 1 isdissolved in 100 ml. of anhydrous methanol. One mole of anhydrous NH₃ iscondensed in over a period of 40 minutes. (A dry ice-acetone condenseris used to prevent ammonia loss during reaction). After stirring for 0.5hr., the dry ice-acetone condenser is removed and excess NH₃ is allowedto volatilize (20-30 minutes). The precipated NH₄ Cl is filtered off(13.2 gmo, 0.246 mole, 62%) and the filtrate is concentrated to leave aviscous oil (43 gm.) which contains 58% by weight freedl-2-amino-1-butanol (the remainder being unreacted dl-2-amino-1-butanolhydrochloride).

The mixture (42 g.) is dissolved in 120 ml. of anhydrous methanol andthe solution is treated with 35 g. (0.233 mole) of L(+)-tartaric acid.The reaction temperature rises to 45°-47° C. during addition of tartaricacid. The solution is maintained at this temperature for 1 hour and thencooled to 25° C. over a period of 4-5 hours. Crystallization can beexpedited by seeding the solution with d-2-amino-1-butanol L(+)-tartrateto induce crystallization of the salt.

The precipitated salt is filtered off and washed four times with coldmethanol and then dried in an inert atmosphere. The salt is obtained ascolorless crystalline solid [30 g., 0.125 mole, 63%) mp. 138°-140° C.[α]² _(D) ⁶ = 23.52° (c = 5%, H₂ O)] and in a typical run wasindistinguishable from authentic d-2-amino-1-butanol L(+)-tartrate [mp.137°-141° C.; [α]² _(D) ⁶ = 23.74° (c = 5%, H₂ O)]. Up to about 8% ofdl-1-amino-2-butanol may be formed in the reactions from the addition ofthe imido group to the 1 position in butene-1, in effect, the reverse ofthat desired. By analogous reactions, this is converted todl-1-amino-2-butanol. Both the d and l isomers remain with the motherliquor in the crystallization, and permit the separation ofd-2-amino-1-butanol L(+)-tartrate substantially free from impurities.

The isolation of d-2-amino-1-butanol from the salt has been described inU.S. Pat. No. 3,553,257, supra.

Conversion to ethambutol is described in 3,769,347, supra.

EXAMPLE 4 d-2-Amino-1-butanol

d-2-Amino-1-butanol tartrate (150 g.) (0.63 mole) from Example 3 isadded with stirring to an aqueous solution of KOH prepared by dissolving76 g. KOH in 115 ml. of distilled water. d-2-Amino-1-butanol which formsthe upper layer is extracted with tetrahydrofuran (100 ml. × 2). Thetetrahydrofuran extract is dried (Na₂ SO4) and concentrated underreduced pressure. The crude, oily residue is distilled under reducedpressure to give d-2-amino-1-butanol (b.p. 99°-103° at 30 mm.). Thematerial is further fractionated to give pure d-2-amino-1-butanol havinga b.p. of 174°, and [α]² _(D) ⁵ = 9.9. The yield of the distilledmaterial is about 50% to 76% and can be improved substantially ifadditional extractions are carried out with tetrahydrofuran.

EXAMPLE 5 Ethambutol Hydrochloride

Following the procedure described in Example 1 of U.S. Pat. No.3,769,347, a mixture of 462 g. of d-2-amino-1-butanol, produced inaccordance with the procedure of Example 4, and 32 g. of ethylenedichloride is heated to 80° C. and the temperature is allowed to riseexothermally to about 130° C. After 1 hour, the mixture is cooled toabout 95° C., 22.5 g. of sodium hydroxide is slowly added, and atemperature of about 112° C. is maintained for 1 hour. The sodiumhydroxide is in the form of prills of about 4 mm. diameter. The mixtureis cooled to 70° C. and unreacted d-2-amino-1-butanol is recovered byvacuum distillation. The distillation is at a pressure below 20 mm.mercury, and below 130° C., heat being applied at a rate within thecapacity of the condenser.

Isopropanol (290 g.) is added to the distillation residue at atemperature not above 90° C., and followed by a refluxing period of 30minutes. The mixture is cooled to and filtered at 60° C. to removesodium chloride, and the filter cake is washed with 47 g. ofisopropanol, at 60° C. The volume of the filtrate is diluted to 430 ml.with isopropanol and the temperature is adjusted to 40°-45° C., 2 g. ofdiatomaceous earth filter aid is added, and a second filtration iscarried out.

To the clear filtrate there is added 120 g. of methanol and 15 g. ofwater. The vessel is closed and hydrogen chloride (about 25 g.) isintroduced over the surface of the charge at a gas pressure of 5-7p.s.i.g. while the temperature is allowed to rise to 55° C., to a pH of2 to 2.5. The charge is cooled very slowly to 28° C. and is stirred forabout 1 hour.

Conveniently, a small aliquot is titrated, and a calculated quantity ofhydrogen chloride added. Proper final pH is confirmed by testing as acidto wet Congo Red test paper. Other methods of measuring the pH can beused. The white crystalline product,d,d'-2,2'-(ethylenediimino)-di-1-butanol dihydrochloride is separated byfiltration and washed with isopropanol. The product, carefully dried ata maximum temperature of 75° C., is about 70 g., has a decompositionrange of 198.5°-204° C., and an ash content of 0.1%.

This is a pharmaceutically acceptable, elegant grade of ethambutolhydrochloride without further treatment or refinement. The product maybe tabletted or encapsulated by conventional procedures.

EXAMPLE 6 N-[1-(Chlormethyl)propyl]acetamide

Into a 250 ml. 3-necked flask fitted with a stirrer, dry ice-acetonetrap, a gas outlet, and a gas inlet is charged 41.05 g. (1.0 mole)acetonitrile, 25 g. (0.25 mole) CaCO₃, 13.5 ml. (0.75 mole) water and26.8 g. (0.475 mole) 1-butene. The mixture is cooled to -5° to -8° C.and chlorine added over 2 hours maintaining the temperature at below 7°C. until the reaction mixture turns yellow indicating a slight excess ofchlorine. The mixture is filtered and the solvents distilled underreduced pressure to yield 28.6 g. of N-[1-(chloromethyl)propyl]acetamide(40.2% yield based on 1-butene).

EXAMPLE 7 N-[1-(Chloromethyl)propyl]acetamide

A 500 ml. 3-necked flask fitted with a stirrer and dry ice-acetone trapis charged with 82.1 g. (2.0 mole) acetonitrile, 27.4 g. (1.52 mole)water, 27 g. (0.25 mole) Na₂ CO₃ and 28.1 g. (0.50 mole) 1-butene andcooled to 0° C. Chlorine (0.50 mole) is added over one-half hour, thereaction temperature reaching a high of 32° C. After stirring for 2hours at 25° C., the reaction mixture is filtered. The acetonitrilewashings of the solid phase and filtrate is combined and the solventsremoved by vacuum distillation to leave 33.0 g. of theN-[1-(chloromethyl)propyl]acetamide (44.0% yield based on 1-butene).

EXAMPLE 8 dl-2-Amino-1-butanol

Sodium hydroxide pels (97% pure, 18.8 g. 0.45 mole) are stirred with 100ml. of anhydrous methanol and crude dl-2-amino-1-butanol hydrochloride50 g. (87% real. 0.35 mole) from a run similar to that of Example I isadded with stirring over a period of 0.5 hr. The reaction mixture warmsup and precipitated sodium chloride is removed by filtration, washedwith methanol and the washings combined with the main filtrate. Methanoland water (formed during neutralization) are removed under reducedpressure and the residual oil distilled to yield dl-2-amino-1-butanol(b.p. 95°-100°/30-35 mm.), 26.68 g. (86% of theory). The materialcontains about 9.6% of dl-1-amino-2-butanol.

dl-2-Amino-1-butanol can be used as a catalyst as described in U.S. Pat.No. 3,539,652 (CA 74, 23499) as a component of organosiliconecompositions, French Pat. No. 1,556,008 (CH71, 115) or as a component ina flame retardant composition U.S. Pat. No. 3,413,380 (CA 70, 40).

EXAMPLE 9 dl-2-Amino-1-butanol

Sodium hydroxide pels (97% pure, 18.8 g. 0.45 mole) are stirred with 100ml. of isopropanol containing 0.7 ml. of water. A part of the sodiumhydroxide goes into solution. Crude dl-2-amino-1-butanol hydrochloride50 g. (70% real, 0.28 mole) is added with stirring over a period of 0.5hr. The reaction mixture warms up to about 45° C. and crystalline sodiumchloride precititates out of the reaction mixture. The salt is removedby filtration, washed with isopropanol and the washings are combinedwith the main filtrate. The filtrate is distilled under reducedpressure. Isopropanol and water are removed as a fore-run anddl-2-amino-1-butanol (25 g. 88.3% yield) is distilled at 95°-105°at 30mm. Gas liquid chromatographic analysis of this product showed it tocontain about 10% 1-amino-2-butanol.

EXAMPLE 10 d-2-Amino-1-butanol

To a 15 g. portion of undistilled crude dl-2-amino-1-butanol (59% real,0.1 mole) from a run similar to that of Example 2, dissolved in 48 ml.of methanol is added with stirring 17.5 g. (0.117 mole) of L(+)-tartaricacid while the temperature is maintained at 45°. The solution is seededwith a small amount of crystals of the L(+)-tartrate ofd-2-amino-1-butanol and the temperature maintained at 45° C. for 0.5 hr.An additional 4.2 g. (0.028 mole) of tartaric acid is added and themixture held at 45°-47° C. for an additional 0.5 hour. The temperatureis then lowered to 16°-18° over a 4 hour period and held at thistemperature for 1 hour. The crystalline L(+)-tartrate ofd-2-amino-1-butanol lis removed by filtration, washed with cold methanol(3 ml. × 3) and dried in an inert atmosphere. In one such run thed-2-amino-1-butanol L(+)-tartrate weighed 8.5 (0.035 mole, 71.0%),melted at 137°-138° and had a specific rotation [α ² _(D) ⁶ = 23.74 (c -5%, H₂ O). The crude feed dl-2-amino-1-butanol contained about 8% ofdl-1-amino-2-butanol as an impurity. This impurity is not carriedthrough the resolution process. The L(+)-tartrate salt ofd-2amino-1-butanol obtained after resolution is found to contain nodetectable quantities of 1-amino-2-butanol, by gas liquidchromatography, which is sensitive to about 0.01% of 1-amino-2-butanol.

EXAMPLE 11 d-2-Amino-1-butanol

To 15 g. of distilled dl-2-amino-1-butanol (88.5% pure by gas liquidchromatography), from a run similar to Example 2, dissolved in 48 ml. ofanhydrous methanol is added with stirring 17.5 g. (0.117 mole) ofL(+)-tartaric acid while maintaining the temperature below 47° C. Theresulting solution is stirred at 45°-47° for 0.5 hour and an additional4.21 g. (0.028 mole) of tartaric acid is added and the solution stirredfor an additional 0.5 hour at 45-47%. The solution is seeded with asmall amount of the L(+)-tartrate of d-2-amino-1-butanol. The mixture isslowly cooled to 16°-17° C. over a 4 hour period and the crystallineL(+)-tartrate salt of d-2-amino-1-butanol is removed by filtration,washed with cold methanol (3 ml. × 3) and dried in an inert atmosphere.The white crystalline material (14.5 g., 0.061 mole 81.9% yield) meltsat 136°-140° and has a specific rotation of [α]² _(D) ⁵ = 23.74 (c = 5%,H₂ O). The feed dl-2-amino-1-butanol used for resolution contains about8 % of dl-1-amino-2-butanol as an impurity. This impurity is, however,not carried through the resolution process. The L(+)-tartrate salt ofd-2-amino-1-butanol obtained after resolution is found to contain nodetectable quantities of either d or l 1 -amino-2-butanol by gas liquidchromatography which is sensitive to 0.01% of 1-amino-2-butanol.Apparently, all of the dl-1-amino-2-butanol remains with the motherliquor, and is rejected along with the 1-2-amino-1-butanol in themethanol.

EXAMPLE 12 dl-2-Amino-1-butanol

A. A 137-g. sample of crude dl-2-amino-1-butanol hydrochloride from arun similar to Example I is treated with a solution of 137 g. KOH in 200ml. of water. The mixture is extracted three times with tetrahydrofuranand the combined extracts dried (Na₂ SO₄ ). The solvent is removed underreduced pressure to give 95 g. of a crude oil (60.6%dl-2-amino-1-butanol and 6% dl-1-amino-2-butanol).

B. In a separate experiment a 250-g. sample of similar crudedl-2-amino-1-butanol hydrochloride dissolved in 200 ml. of anhydrousmethanol is treated with 3 moles of anhydrous ammonia. After a few hoursstirring, the excess ammonia is allowed to evaporate. The precipitatedammonium chloride is removed by filtration and the filtrate concentratedgives 174.5 gm. of an oil which contains both dl-2-amino-1-butanol andits hydrochloride together with some quantities of dl-1-amino-2-butanoland its hydrochloride (total 58.9% dl-2-amino-1-butanol by gas liquidchromatography.

C. A 7.5-gm. sample of crude dl-2-amino-1-butanol from the firstexperiment (A) is mixed with a 7.5 gm. portion of the material(dl-2-amino-1-butanol and its hydrochloride) from the second experimentand the mixture is dissolved in a mixture of 80 parts of anhydrousmethanol and 20 parts of isopropanol (v/v) (the solution contains 0.1mole of real dl-2-amino-1-butanol of which 0.097 mole is present as thefree base). L(+)-tartaric acid (15 g., 0.1 mole) is added slowly keepingthe temperature below 45° C. until the exotherm ceases. After stirringthe solution for an hour at 45° C., the temperature is lowered slowlyand at 40° C. the mixture is seeded with a small amount of theL(+)-tartrate salt of d-2-amino-1-butanol and then gradually cooled to18° over a period of 4 hours. The crystalline L(+)-tartrate salt ofd-2-amino-1-butanol formed in the reaction mixture is removed byfiltration, washed with cold methanol (3 ml. × 3) and pumped dry. Theyield of the material is 9.0 g. (0.036 mole, 75.2%); m.p., 137.5-139.5;[α ² _(D) ⁵ = 23.84° (c = 5%, H₂ O).

EXAMPLE 13 N-[1-(Chloromethyl)propyl]acetimidoyl chloride

Reagent grade acetonitrile (82 g., 2 moles) is placed in a 500 ml.three-necked flask equipped with a mechanical stirrer, a low-temperaturethermometer and two fritted inlet tubes. With vigorous stirring andcooling (-20° C.), butene-1 (28 g. 0.5 mole) and chlorine (35.5 g., 0.5mole) are added simultaneously both at a rate of about 375-400 ml./min.The addition is complete in about 37 minutes and the reactiontemperature at the end of this period rises to -10° C. (bath/20° C.) Themixture is fractionated to give: Fraction I, 89 g. (mostly acetonitrile)distilling under 20 mm. pressure at a bath temperature of 50° C.;Fraction II, 12.5 g. distilling under 20 mm. pressure at a bathtemperature of 65° C., 70% 1,2-dichlorobutane, 30%N-[1-chloromethyl)propyl]acetimidoyl chloride; Fraction III, 35.9 g.distilling under 2 mm. pressure at a bath temperature of 60°, about 90%N-[1-chloromethyl)propyl]acetimidoyl chloride residue, 6.7 g. dark brownviscous oil. Based on Fractions II and III, the yield ofN-[1-(chloromethyl)propyl]acetimidoyl chloride is 39.7 g. (48%). Aportion of Fraction III is redistilled to give a pale yellow oil with acharacteristic odor resembling that of thionyl chloride. The product,N-[1-(chloromethyl)propyl]acetimidoyl chloride displays strong infraredbands at 3000, 1705, 1430, 1370, 1085, 960, 920, 840 and 740 cm⁻ ¹.NMR(CDCl₃): 0.88 ppm (t ,3H), 1.4-1.8 ppm (m ,2H), 245 ppm (s ,3H), 3.62ppm (m ,2H,--CH₂ Cl), and about 3.9 ppm (m ,1H, CH).

Occasionally, a solid isomer of N-[1-(chloromethyl)propyl]acetimidoylchloride (often the major product) is also obtained. The two forms seento be interconvertible in certain solvents. On reaction with water, bothhydrolyze to N-[1-chloromethyl)propyl]acetamide. The solid form hasinfrared bands at 3000, 1650, 1550, 1480, 1365, 1280, 1045, and 740 cm⁻¹.

EXAMPLE 14 N-[1-(Chloromethyl)propyl]acetamide

A sample of N-[1-chloromethyl)propyl]acetimidoyl chloride from Example 8is treated with an excess of 10% aqueous sodium carbonate solution atroom temperature. The organic material is extracted with ether and driedover MgSO4. Removal of the solvent under reduced pressure leavesN-[1-(chloromethyl)dropyl]acetamide as a crystalline solid in nearlyquantitative yield. An infrared spectrum shows peaks at 3300(M),3100(W), 1650(S), and 550(S) cm⁻ ¹ ; nuclear magnetic resonance (CDCl3)shows peaks 0.95 ppm (t ,3H), 1.4-1.8 ppm (m ,2H), 2.03 ppm (s ,3H),3.67 ppm (d,2H,CH₂ Cl), 3.8-4.4 ppm (m ,1H).

The effects of conditions on yields is shown in the following examplesin which the chlorination reactions were carried out at initialtemperatures of -3° to +23° and the acetonitrile to Cl₂ ratio was variedfrom 2 to 4. Additionally, the initial concentration of butene-1 wasvaried by either passing butene-1 and Cl₂ simultaneously (low initialbutene-1 concentration) into acetonitrile or by first condensing buteneat -5° C. into acetonitrile and then passing Cl₂ through the mixture(high initial butene-1 concentration). The results of these experimentsin Table I show that the yield of N-[1-(chloromethyl)propyl]acetimidoylchloride is dependent primarily on the mole ratio of acetonitrile to Cl₂and amounts to about 50-55% when this ratio approaches 4.

                                      TABLE I                                     __________________________________________________________________________    PRODUCTION OF N-[1-(CHLOROMETHYL)PROPYL]ACETIMIDOYL CHLORIDE (I)              Reaction of Butene-1 (0.5 mole) with Cl.sub.2 (0.5 mole) in                   Acetonitrile.sup.a (AN)                                                              T° C AN/Cl    Cl.sub.2 Rate                                                                        Reaction Time                                                                           Initial Butene                                                                          I                      Example                                                                              Init. Peak  (mole ratio)                                                                           (ml/min)                                                                             (hrs.)    conc.     (%                     __________________________________________________________________________                                                           yield).sup.d           15     0     3     2        100    2         high.sup.b                                                                              36                     16     0     17    2        100    2         low.sup.c 37.8                   17     23    27    4        400    0.5       low.sup.c 57.0                   18     -2    20    4        400    0.5       high.sup.b                                                                              43.8                   19     -3    32    4        400    0.5       high.sup.b                                                                              48.0                   20     0     5     4        400    0.5       high.sup.b                                                                              54.0                   21     0     5     4        100    2.0       low.sup.c 55.0                   __________________________________________________________________________     .sup.a All reactions were carried out in a Morton flask under vigorous        stirring and at atmospheric pressures.                                        .sup.b Butene-1 was charged to reaction flask by pouring a weighed sample     into acetonitrile cooled to -5°C.                                      .sup.c Butene-1 and Cl.sub.2 were simultaneously passed via calibrated        flowmeters.                                                                   .sup. d Yields were based on actual weights of the residues left after        distilling off the volatiles. Product purity was checked by gas liquid        chromatography, infrared, and nuclear magnetic resonance.                     I I = N-[1-(chloromethyl)propyl]acetimidoyl chloride.                    

Hydrolysis of N-[1-(chloromethyl)propyl]acetimidoyl chloride is highlypH dependent. It has now been found that a simple hydrolysis procedureis effective. On refluxing with waterN-[1-(chloromethyl)propyl]acetimidoyl chloride is transformed into amixture of dl-2-amino-1-butanol (77%), dl-2-amino-1-butanol acetatehydrochloride (17%), the N-[1-(hydroxymethyl)propyl]acetamide (7%) andacetic acid within one hour. The product ratios appear to representequilibrium compositions because additional heating (14 hrs.) does notmaterially change their distribution. If, however, the hydrolysis iscarried out with aqueous methanol or ethanol, it is complete within 2hours and the acetyl component of the product can be removed as methylor ethyl acetate by distillation. This procedure not only decreaseshydrolysis time, it also avoids the accumulation of salts in thereaction mixture, gives essentially quantitative yields ofdl-2-amino-1-butanol fron N-[1-(chloromethyl)propyl]acetimidoyl chloridethrough N-[1-(chloromethyl)propyl]acetamide, and facilitates productwork-up. Methyl acetate boils at 57° C., and is readily distilled off.

In order to make this process as economical as possible, excessivelylarge volumes of aqueous methanol should be avoided. If insufficientquantities of water are used (less thanN-[1-(chloromethyl)propyl]acetimidoyl chloride:H₂ O:MeOH mole ratio1:3:3) and especially if the hydrolysis is carried out in the presenceof the 1,2-dichlorobutane by-product, a small fraction (3-15%) ofN-[1-(chloromethyl)propyl]acetimidoyl chloride hydrolyzes to2-amino-1-chlorobutane hydrochloride. The formation of2-amino-1-chlorobutane hydrochloride can be totally suppressed if waterand methanol are added sequentially, and in that order, rather thantogether in one step. Addition of water toN-[1-(chloromethyl)propyl]acetimidoyl chloride almost instantaneouslyconverts it to the N-[1-(Chloromethyl)propyl]acetamide which thenhydrolyzes via the oxazoline intermediate.

Three series of reactions (A, B, and C) were completed using as-isacetonitrile (water conc. (Karl-Fisher) = 0.059-0.2%). In each of theseseries, reactions were carried out using 0.5 mole of butene, 0.5 mole ofchlorine, and the acetonitrile:Cl₂ mole ratio (identical to theacetonitrile:butene) was varied from 1 to 8.

In series A (reaction time = 1 hr.) the reaction temperature wasmaintained at 0° C. while chlorine and butene were passed simultaneouslyinto acetonitrile in one hour. After removal of acetonitrile (40°-50°,50 mm), the crude reaction mixture containingN-[1-(chloromethyl)propyl]acetimidoyl chloride and 1,2-dichlorobutanewas hydrolyzed by refluxing with aqueous methanol.

                                      TABLE II                                    __________________________________________________________________________                                         % yield of crude                                  Moles                                                                             AN.sup.a /Butene/Cl.sub.2                                                              Cl.sub.2 Rate                                                                       Reaction Time                                                                          2-amino-1-butanol                        Example                                                                            T° C.                                                                      Butene                                                                            Mole Ratio                                                                             (ml/min)                                                                            (hrs.)   hydrochloride                            __________________________________________________________________________    22   0°                                                                         1.0 1:1:1    400   1.0      31.6                                     23   0°                                                                         0.5 2:1:1    200   1.0      43.6                                     24   0°                                                                         0.5 4:1:1    200   1.0      52.5                                     25   0°                                                                         0.5 6:1:1    200   1.0      61.0                                     26   0°                                                                         0.5 8:1:1    200   1.0      67.0                                     __________________________________________________________________________     .sup.a AN = Acetonitrile                                                 

It is significant to note that N-[1-(chloromethyl)propyl]acetimidoylchloride can be hydrolyzed substantially quantitatively toN-[1-(chloromethyl)propyl]acetamide, and then to dl-2-amino-1-butanol.Reporting as dl-2-amino-1-butanol hydrochloride is a very convenientmethod of showing yields. Errors due to volatile components are avoided.Small quantities of dl-1-amino-2-butanol report with thedl-2-amino-1-butanol. Even at a low acetonitrile:Cl₂ ratio of one, theyield of dl-2-amino-1-butanol.sup.. HCl is as high as 31%. Increasingthe acetonitrile:Cl₂ mole ratio from 1 to 2 improves the yield to 43%,an increase of 12%. Further increases in the acetonitrile:Cl₂ ratiosalso improve the yields. For each additional mole of acetonitrile(up toa total of 5 moles (AN:Cl₂ ratios 3 to 5) the yield ofdl-2-amino-1-butanol.sup.. HCl increases on average about 6%. Stillfurther addition of acetonitrile (AN:Cl₂ mole ratios 6 to 8) isconsiderably less effective; the average incremental yield ofdl-2-amino-1-butanol.sup.. HCl being of the order of about 3% per moleof acetonitrile. A ratio of about 4:1 is a good compromise between yieldand a reasonable size reaction vessel and recycle ratio of acetonitrile.

In both series B and C, the gaseous reactants were run into acetonitrileover a period of 0.5 hr. The initial reaction temperature was 0°. Thiswas allowed to rise to a maximum of 35° during the course of thereaction. Additionally, in series B, chlorine was passed through asolution of butene in acetonitrile to maintain a high initialconcentration of butene. In series C both chlorine and butene werepassed simultaneously through acetonitrile allowing attainment of a lowinitial concentration of butene. The results of simultaneous andsequential additions of butene and chlorine on the yield ofN-[1-chloromethyl)propyl]acetimidoyl chloride at differentacetonitrile/Cl₂ mole ratios are summarized in Table III.

                                      TABLE III                                   __________________________________________________________________________    Reaction of Butene-1 (0.5 mole).sup.a with Cl.sub.2 (0.5 mole).sup.a in       Acetonitrile (AN)                                                             Series B.sup.b : Addition of Cl.sub.2 to Butene + Acetonitrile (AN)                                               N-1-(chloromethyl)-                                       N-[1-(chloromethyl)-                                                                      1,2-dichlo-                                                                           propyl]acetimidoyl                                                                         % aceto-                              AN:Cl.sub.2                                                                          propyl]acetimidoyl                                                                        robutane                                                                              chloride + 1,2-dichlo-                                                                     nitrile                      Example                                                                            T° C.                                                                      (mole ratio)                                                                         chloride    (moles) robutane (moles)                                                                           recovery                     __________________________________________________________________________                    Moles %.sup.c       Exp.   Theor.                             27   0-35                                                                              1.1    0.164 32.3  0.350   0.514  0.5   90                           28   0-30                                                                              1.5    0.162 32.6  0.340   0.502  0.5   92                           29   0-25                                                                              2      0.192 38.0  0.310   0.502  0.5   97                           30   0-23                                                                              4      0.223 45.3  0.250   0.473  0.5   95                           31   0-25                                                                              4      0.241 47.8  --      --     --    --                           32   0-23                                                                              6      0.291 57.6  0.270   0.561  0.5   94                           33   0-15                                                                              8      0.269 54.3  0.180   0.459  0.5   99                           Series C.sup.b : Simultaneous Addition of Cl.sub.2 and Butene to              Acetonitrile                                                                  34   0-25                                                                              1      0.74  35.6  1.26    2.00   2.0   102                          35   0-24                                                                              2      0.222 43.9  0.270   0.492  0.5   99                           36   0-27                                                                              4      0.246 47.1  0.270   0.516  0.5   99                           37   0-22                                                                              6      0.281 54.0  0.240   0.521  0.5   97                           38   0-21                                                                              8      0.337 66.0  0.130   0.467  0.5   99                           __________________________________________________________________________     .sup.a Except in Example 34 where 2 mole of Cl.sub.2 and 2 mole of butene     were passed through 2 moles of acetonitrile over a two-hour period.           .sup.b Reaction time: 0.5 hr; Cl.sub.2 rate: 400 ml/min                       .sup.c Yields based on butene. These percentages do not include losses of     N-[1-(chloromethyl)propyl]acetimidoyl chloride during removal of              1,2-dichlorobutane by distillation which may amount to 3-5%.             

In series B and C material balances show conversion and recovery data onacetonitrile. In each case the distillate, 1,2-dichlorobutane +acetonitrile was analyzed for 1,2-dichlorobutane and acetonitrile by gasliquid chromatography.

A less pure product is obtained if theN-[1-(chloromethyl)propyl]acetimidoyl chloride is allowed to stand for40-50 hours prior to work-up.

The data in the table shows that:

1. The yield of crude dl-2-amino-1-butanol.sup.. HCl (orN-[1-(chloromethyl)propyl]acetimidoyl chloride) is primarily dependenton the mole ratio of acetonitrile:Cl₂ and varies between 31 and 66% asthe acetonitrile:Cl₂ :butene mole ratio changes from 1:1:1 to 8:1:1.

2. Simultaneous addition of chlorine and butene to acetonitrile ratherthan the alternate procedure of adding chlorine to a mixture of buteneand acetonitrile is advantageous. The reaction is less exothermic,consequently easier to control, and the yields ofdl-2-amino-1-butanol.sup.. HCl are somewhat better. A reaction time ofone hour generally appears to permit more control over the reactionexothermicity.

3. The reaction temperature does not appear to be controlling factor indetermining the overall yield. However, in view of the thermalinstability of N-[1-(chloromethyl)propyl]acetimidoyl chloride) above50°, reaction temperatures between 0°-25° are more desirable.

The process can vary depending on the size of batches. Whereas theExamples are exemplary, for large scale production, the process may berun continuously, with the butene-1 and chlorine being fed continuouslyto a stirred continuous reactor. The recycle acetonitrile is distilledoff and recycled continuously. Such a continuous system permits a higherratio of acetonitrile to the butene-1 and chlorine. Whereas, for a batchprocess, a molar ratio of at least 2 of acetonitrile to butene-1 andchlorine is preferred, more than a ratio of 16 can require anuneconomically large reactor. With a continuous process even higherratios are convenient.

Whereas both butene-1 and chlorine are gaseous at room temperature ofabout 20° C., so that low temperatures, around 0° C. and lower areconvenient, a higher temperature to reduce the need for cooling may beused if a pressurized reactor is available.

The trade-off of the cost of a pressure reactor against additionalrefrigeration can vary with equipment available.

Other modifications within the scope of this invention as defined by theappended claims are, of course, obvious to those skilled in the arts.

I claim:
 1. A process for the isolation of d-2-amino-1-butanol fromdl-2-amino-1-butanol containing up to about 10% of dl-1-amino-2-butanolwhich comprises forming a solution of said dl-2-amino-1-butanolcontaining dl-1-amino-2-butanol in anhydrous methanol, adding theretoL(+)-tartaric acid in at least about one-half molar quantity, andseparating the crystalline acid L(+)-tartrate salt ofd-2-amino-1-butanol from the methanol containing 1-2-amino-1-butanol andboth d- and l- 1-amino-2-butanol.
 2. The process of claim 1 in which thedl-2-amino-1-butanol is synthesized by heatingN-[1-(chloromethyl)propyl]acetamide in the presence of a lower alkanoland water whereby the N-[1-(chloromethyl)propyl]acetamide is hydrolyzedto dl-2-amino-1-butanol hydrochloride and distilling off the coproducedalkanol acetate, whereby side reactions are suppressed, and thehydrolysis to dl-2-amino-1butanol hydrochloride is essentiallyquantitative.
 3. The process of claim 2 in which the lower alkanol ismethanol, and the dl-2-amino-1-butanol is separated as the hydrochloridesalt.
 4. The process of claim 2 in which theN-[1-(chloromethyl)propyl]acetamide is synthesized by reactingN-[1-(chloromethyl)propyl]acetimidoyl chloride with water, therebyhydrolyzing N-[1-(chloromethyl)propyl]acetimidoyl chloride toN-[1-(chloromethyl)propyl]acetamide.
 5. The process of claim 2 in whichthe N-[1-(chloromethyl)propyl]acetamide is synthesized by reacting atleast about 2 moles of acetonitrile with about 1 mole of chlorine andabout 1 mole of butene-1, to produceN-[1-(chloromethyl)propyl]acetimidoyl chloride with the concurrentproduction of 1,2-dichlorobutane, adding water, thereby hydrolyzing saidN-[1-(chloromethyl)propyl]acetimidoyl chloride toN-[1-(chloromethyl)propyl]acetamide, and after the synthesis of saidN-[1-chloromethyl)propyl]acetamide, distilling off under reducedpressure and recovering the excess acetonitrile.
 6. The process of claim5 in which water is added at about the same rate asN-[1-(chloromethyl)propyl]acetimidoyl chloride is produced, therebyhydrolyzing N-[1-(chloromethyl)propyl]acetamide before saidN-[1-(chloromethyl)propyl]acetimidoyl chloride can be additionallychlorinated, and also releasing the heat of hydrolysis over the courseof the reaction, thus controlling isothermal temperature rise.
 7. Theprocess of claim 6 in which the separated acetonitrile is recycledwithout additional purification.
 8. The process of claim 7 in which theaddition of butene-1, chlorine and water to acetonitrile is a continuousprocess, and the recycling of acetonitrile is continuous.
 9. The processof claim 5 in which the chlorine, butene-1 and water are addedconcurrently.
 10. The process of claim 5 in which butene-1 is addedfirst, and then chlorine and water are added.
 11. The process of claim 1in which about one-third of the dl-2-amino-1-butanol is present as thehydrochloride salt.
 12. The process of claim 5 in which the water ispresent with the acetonitrile before the addition of chlorine.
 13. Inthe production of dl-2-amino-1-butanol, or one of its optical isomers,as the free base, from the hydrochloride, the improvement comprising theprocess of adding an excess of NH₃ to precipitate HCl as NH₄ Cl,evaporating off excess NH₃, and separating out the NH₄ Cl, whereby thereis neither excess NH₃ or HCl remaining in the product free base ofdl-amino-1-butanol, or one of its optical isomers.
 14. In the productionof dl-2-amino-1-butanol, or one of its optical isomers, as the freebase, from the hydrochloride, the improvement comprising the process ofadding an excess of NH₃ to precipitate HCl as NH₄ Cl, separating out theNH₄ Cl, and evaporating off the excess NH₃, whereby there is neitherexcess NH₃ or HCl remaining in the product free base ofdl-amino-1-butanol, or one of its optical isomers.